US5210092A - Angiotensin ii antagonizing heterocyclic derivatives - Google Patents

Angiotensin ii antagonizing heterocyclic derivatives Download PDF

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Publication number
US5210092A
US5210092A US07/748,954 US74895491A US5210092A US 5210092 A US5210092 A US 5210092A US 74895491 A US74895491 A US 74895491A US 5210092 A US5210092 A US 5210092A
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nmr
imidazo
cdcl
methyl
pyridine
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Inventor
Teruo Oku
Hiroyuki Setoi
Hiroshi Kayakiri
Shigeki Satoh
Takayuki Inoue
Yuki Saitoh
Akio Kuroda
Hirokazu Tanaka
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Fujisawa Pharmaceutical Co Ltd
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Fujisawa Pharmaceutical Co Ltd
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Priority claimed from GB909020838A external-priority patent/GB9020838D0/en
Priority claimed from GB909023467A external-priority patent/GB9023467D0/en
Priority claimed from GB909028216A external-priority patent/GB9028216D0/en
Priority claimed from GB919103874A external-priority patent/GB9103874D0/en
Priority claimed from GB919106956A external-priority patent/GB9106956D0/en
Priority claimed from GB919107231A external-priority patent/GB9107231D0/en
Priority claimed from GB919112803A external-priority patent/GB9112803D0/en
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Priority to US07/758,688 priority Critical patent/US5215994A/en
Assigned to FUJISAWA PHARMACEUTICAL CO., LTD. reassignment FUJISAWA PHARMACEUTICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: OKU, TERUO, INOUE, TAKAYUKI, KAYAKIRI, HIROSHI, KURODA, AKIO, SAITOH, YUKI, SATOH, SHIGEKI, SETOI, HIROYUKI, TANAKA, HIROKAZU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel heterocyclic derivatives and a pharmaceutically acceptable salt thereof. More particularly, it relates to novel imidazole derivatives and a pharmaceutically acceptable salt thereof which have pharmacological activities such as angiotensin II antagonism and the like, to process for preparation thereof, to a pharmaceutical composition comprising the same and to a use of the same as a medicament.
  • one object of the present invention is to provide novel imidazole derivatives and a pharmaceutically acceptable salt thereof, which are useful as a potent and selective antagonist of angiotensin II
  • Another object of the present invention is to provide process for preparation of said imidazole derivatives or a salt thereof.
  • a further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said imidazole derivatives or a pharmaceutically acceptable salt thereof.
  • Still further object of the present invention is to provide a use of said imidazole derivatives or a pharmaceutically acceptable salt thereof as a medicament such as angiotensin II antagonist useful for treating or preventing angiotensin II mediated diseases, for example, hypertension (e.g. essential hypertension, renal hypertension, etc.), heart failure, and the like in human being or animals.
  • angiotensin II antagonist useful for treating or preventing angiotensin II mediated diseases, for example, hypertension (e.g. essential hypertension, renal hypertension, etc.), heart failure, and the like in human being or animals.
  • the imidazole derivatives of the present invention are novel and can be represented by the formula (I): ##STR2## wherein R 1 is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino,
  • R 2 , R 3 and R 4 are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, more or di or trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl or optionally esterified carboxy; or
  • R 2 and R 3 are linked together to form 1,3-butadienylene
  • R 5 is hydrogen or imino-protective group
  • A is lower alkylene
  • X is N or CH
  • Y is NH, O or S, and ##STR3## is condensed or uncondensed imidazolyl which may have suitable substituent(s).
  • the object compound (I) can be prepared by the following processes. ##STR4## Wherein R 1 , R 2 , R 3 , R 4 , R 5 , A, Q, X, Y and are each as defined above,
  • R a 4 is oxo(lower)alkyl or halogen
  • R b 4 is hydroxy(lower)alkyl or hydrogen
  • R 6 is acid residue.
  • Suitable salts of the compound (I) are conventional non-toxic, pharmaceutically acceptable salt and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g. sodium salt, potassium salt, cesium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g.
  • triethylamine salt pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), etc.
  • an inorganic acid addition salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an organic carboxylic or sulfonic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.
  • a salt with a basic or acidic amino acid e.g. arginine, aspartic acid, glutamic acid, etc.
  • the preferable example thereof is an acid addition salt.
  • lower is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.
  • Suitable "lower alkyl” and lower alkyl group in the term “lower alkylthio” may include straight or branched one, having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, preferably one having 1 to 5 carbon atoms, and the like.
  • Suitable "lower alkenyl” may include vinyl, 1-propenyl, allyl, 1-butenyl, 2-butenyl, 2-pentenyl, and the like, preferably one having 2 to 4 carbon atoms, in which the most preferred one is vinyl.
  • Suitable "lower alkylene” is one having 1 to 6 carbon atom(s) and may include methylene, ethylene, trimethylene, propylene, tetramethylene, methyltrimethylene, dimethylethylene, hexamethylene, and the like, in which the preferred one is methylene.
  • halogen means fluoro, chloro, bromo and iodo.
  • Suitable "lower alkoxy” may include straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, in which the preferable one is C 1 -C 4 alkoxy.
  • Suitable acyl group in the term "acylamino" may include carbamoyl, thiocarbamoyl, sulfamoyl, aliphatic acyl, aromatic acyl, heterocyclic acyl, in which the preferable one is aliphatic acyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, hexanoyl, etc.).
  • lower alkanoyl e.g. formyl, acetyl, propionyl, butyryl, hexanoyl, etc.
  • Suitable "mono or di or trihalo(lower)alkyl” may include chloromethyl, fluoromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trifluoromethylpropyl, and the like.
  • Suitable "hydroxy(lower)alkyl” may include hydroxymethyl, hydroxyetyl, and the like.
  • Suitable “oxo(lower)alkyl” may include formyl, formylmethyl, formylethyl, and the like.
  • Suitable "esterified carboxy” may include lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, etc.), and the like.
  • Suitable "imino-protective group” may include conventional one, and the preferable example thereof is ar(lower)alkyl such as mono-(or di- or tri-)phenyl(lower)alkyl (e.g. benzyl, benzhydryl, trityl, etc.), acyl such as lower alkoxycarbonyl (e.g. tert-butoxycarbonyl, etc.), lower alkanesulfonyl (e.g. mesyl, etc.), arenesulfonyl (e.g. tosyl, etc.), and the like, in which the most preferred one is trityl.
  • ar(lower)alkyl such as mono-(or di- or tri-)phenyl(lower)alkyl (e.g. benzyl, benzhydryl, trityl, etc.)
  • acyl such as lower alkoxycarbonyl (e.g. tert-butoxycarbonyl,
  • condensed on uncondensed imidazolyl means 1H-imidazol-1-yl which may be condensed with aromatic or heterocyclic ring, and such group may include benzene, naphthalene, 5 or 6- membered aromatic heteromonocyclic group such as 5 or 6- membered aromatic heteromonocyclic group containing 1 to 2- nitrogen atom(s) (e.g. pyrrole, imidazole, pyrazole, pyridine, pyrimidine, etc.), 5 or 6-membered aromatic heteromonocyclic group containing 1 oxygen atom (e.g. furan, etc.), 5 or 6- membered aromatic heteromonocyclic group containing 1 sulfur atom (e.g. thiophene, etc.), and the like.
  • benzene, naphthalene such as 5 or 6- membered aromatic heteromonocyclic group containing 1 to 2- nitrogen atom(s) (e.g. pyrrole, imidazole, pyrazole,
  • Suitable substituent in the term "condensed or uncondensed imidazolyl which may have suitable substituent(s)" is conventional one used in a pharmaceutical field and may include lower alkyl, halogen, lower alkoxy, hydroxy(lower)alkyl as mentioned above, respectively; optionally esterified carboxy such as carboxy, lower alkoxycarbonyl (e.g. ethoxycarbonyl, etc.); and the like.
  • 2-lower alkyl-3H-imidazo[4,5-b]pyridin-3-yl e.g. 2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl, 2-propyl-3H-imidazo[4,5-b]pyridin-3-yl, 2-butyl-3H-imidazo[ 4,5-b]pyridin-3-yl, etc.
  • 2,7-di(lower)alkyl-3H-imidazo[4,5-b]pyridin-3-yl e.g.
  • Suitable “acid residue” may include halogen e.g. fluoro, chloro, bromo, iodo),acyloxy (e.g. acetoxy, tosyloxy, mesyloxy, etc.) and the like.
  • heterocyclic derivatives (I) of the present invention can be represented by the following chemical formula: ##STR6## wherein R a is lower alkyl
  • R b is hydrogen or lower alkyl
  • A is lower alkylene
  • R 2 , R 3 and R 4 are each hydrogen, halogen or nitro; or
  • R 2 and R 3 are linked together to form 1,3-butadienylene
  • R b is hydrogen or lower alkyl
  • R 1 is hydrogen, halogen, nitro, lower alkoxy, amino or acylamino
  • A is lower alkylene
  • Q is CH or N
  • R 2 , R 3 and R 4 are each hydrogen, halogen or nitro; or
  • R 2 and R 3 are linked together to form 1,3-butadienylene
  • lower alkyl, halogen, lower alkoxy, acylamino and lower alkylene are each the same as those mentioned above.
  • the preferred embodiment of the compound (I) can be represented by the following formula. ##STR8## wherein R 1 is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino,
  • R 2 , R 3 and R 4 are each hydrogen, halogen, nitro, cyano, lower alkyl or lower alkenyl; or
  • R 2 and R 3 are linked together to form 1,3-butadienylene
  • A is lower alkylene
  • Q is CH or N, and ##STR9## is condensed or uncondensed imidazolyl which may have suitable substituent(s),
  • 2-lower alkyl-3H-imidazo[4,5-b]pyridin-3-yl e.g. 2-propyl-3H-imidazo[4,5-b]pyridin-3-yl, 2-butyl-3H-imidazo[4,5-b]pyridin-3-yl, etc.
  • 2,7-di(lower)alkyl-3H-imidazo[4,5-b]pyridin-3-yl e.g.
  • the preferred embodiment of the compound (I) can be represented by the following formula. ##STR11## wherein R 1 is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino,
  • R 2 , R 3 and R 4 are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, dihalo(lower)alkyl, oxo(lower)alkyl or hydroxy(lower)alkyl; or
  • R 2 and R 3 are linked together to form 1,3-butadienylene
  • A is lower alkylene
  • Q is CH or N, and ##STR12## is condensed or uncondensed imidazolyl which may have suitable substituent(s),
  • 2-lower alkyl-3H-imidazo[4,5-b]pyridin-3-yl e.g. 2-propyl-3H-imidazo[4,5-b]pyridin-3-yl, 2-butyl-3H-imidazo[4,5-b]pyridin-3-yl, etc.
  • 2,7-di(lower)alkyl-3H-imidazo[4,5-b]pyridin-3-yl e.g.
  • 2-butyl-3H-imidazo[4,5-d]pyrimidin-3-yl, etc. 2-lower alkyl-1H-thieno[3,4-d]imidazol-1-yl (e.g. 2-butyl-1H-thieno[3,4-d]imidazol-1-yl, etc.), 2-lower alkyl-4-halo-5-hydroxy(lower)alkyl-1H-imidazol-1-yl (e.g. 2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl, etc.); and
  • the preferred embodiment of the compound (I) can be represented by the following formula. ##STR14## wherein R 1 is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino,
  • R 2 , R 3 and R 4 are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono or di or trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl or optionally esterified carboxy; or
  • R 2 and R 3 are linked together to form 1,3-butadienylene
  • R 5 is hydrogen or imino-protective group
  • A is lower alkylene
  • Q is CH or N, and ##STR15## is condensed or uncondensed imidazolyl which may have suitable substituent(s),
  • 2-lower alkyl-3H-imidazo[4,5-b]pyridin-3-yl e.g. 2-propyl-3H-imidazo[4,5-b]pyridin-3-yl, 2-butyl-3H-imidazo[4,5-b]pyridin-3-yl, etc.
  • 2,7-di(lower)alkyl-3H-imidazo[4,5-b]pyridin-3-yl e.g.
  • 2-butyl-3 H-imidazo[4,5-d]pyrimidin-3-yl, etc. 2-lower alkyl-1H-thieno[3,4-d]imidazol-1-yl (e.g. 2-butyl-1H-thieno[3,4-d]imidazol-1-yl, etc.), 2-lower alkyl-4-halo-5-hydroxy(lower)alkyl-1H-imidazol-1-yl (e.g. 2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol- 1-yl, etc.); and
  • R 1 is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino,
  • R 2 and R 3 are each hydrogen, halogen, nitro, cyano, lower alkyl or lower alkenyl; or
  • R 2 and R 3 are linked together to form 1,3-butadienylene
  • A is lower alkylene
  • Q is CH or N, and ##STR18## is condensed or uncondensed imidazolyl which may have suitable substituent(s),
  • 2-lower alkyl-3H-imidazo[4,5-b]pyridin-3-yl e.g. 2-propyl-3H-imidazo[4,5-b]pyridin-3-yl, 2-butyl-3H-imidazo[4,5-b]pyridin-3-yl, etc.
  • 2,7-di(lower)alkyl-3H-imidazo[4,5-b]pyridin-3yl e.g.
  • the preferred compound (I) of the present invention is represented by the following formula: ##STR20## wherein R 2 , R 3 and R 4 and each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono or di or trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl or optionally esterified carboxy (more preferably carboxy or lower alkoxycarbonyl); or
  • R 2 and R 3 are linked together to form 1,3-butadienylene
  • Y is NH, O or S and ##STR21## is 2-lower alkyl-3H-imdazo[4,5-b]pyridin-3-yl, 2,7-di(lower)alkyl-3H-imidazo[4,5-b]pyridin-3-yl, 2,5,7-tri(lower)alkyl-3H-imidazo[4,5-b]pyridin-3-yl, 5-halo-2-lower alkyl-3H-imidazo[4,5-b]pyridin-3-yl, 5-lower alkoxy-2-lower alkyl-3H-imidazo[4,5-b]pyridin-3-yl, 6-lower alkoxycarbonyl-2-lower alkyl-1H-benzimidazol-1-yl, 2-lower alkyl-3H-imidazo[4,5-d]pyrimidin-3-yl, 2-lower alyl-1H-thieno[3,4-d]imidazol-1-yl or 2-lower alkyl-4-
  • ##STR22## is represented by the following formula: ##STR23## wherein R a 2 is hydrogen, halogen, cyano, lower alkyl or lower alkylthio, and
  • R a 3 is hydrogen, halogen, nitro, lower alkyl, lower alkenyl, trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl or lower alkoxycarbonyl; ##STR24## wherein R b 2 and R b 3 are each halogen; ##STR25## wherein R c 2 is hydrogen, halogen or lower alkyl,
  • R c 3 is lower alkyl
  • R c 4 is hydrogen or halogen; ##STR26## wherein R c 2 is hydrogen, halogen or lower alkyl, and
  • R d 3 is lower alkyl; ##STR27## wherein R e 2 is hydrogen or halogen; or ##STR28## and the most preferred one is: ##STR29## wherein R 2 and R 3 are each hydrogen, lower alkyl or halogen.
  • the object compound (I) or a salt thereof can be prepared by subjecting the compound (II) to the formation reaction of a tetrazole group.
  • the agent to be used in the present reaction may include conventional ones which is capable of converting a cyano group to a tetrazolyl group such as metal azide, for example, alkali metal azide (e.g., potassium azide, sodium azide etc.), tri(lower)alkyltin azide (e.g. trimethyltin azide, etc.), triaryltin azide (e.g. triphenyltin azide, etc.), or the like.
  • alkali metal azide e.g., potassium azide, sodium azide etc.
  • tri(lower)alkyltin azide e.g. trimethyltin azide, etc.
  • triaryltin azide e.g. triphenyltin azide, etc.
  • the present reaction is usually carried out in the presence of a base such as tri(lower)alkylamine (e.g. triethylamine, etc.), and the like, or 1,3-dimethyl-2-imidazolidinone, and the like.
  • a base such as tri(lower)alkylamine (e.g. triethylamine, etc.), and the like, or 1,3-dimethyl-2-imidazolidinone, and the like.
  • the present reaction is usually carried out in a solvent such as xylene, dioxane, chloroform, methylene chloride, 1,2-dichloroethane, tetrahydrofuran, pyridine, acetonitrile, dimethylformamide or any other solvent which does not adversely affect the reaction.
  • a solvent such as xylene, dioxane, chloroform, methylene chloride, 1,2-dichloroethane, tetrahydrofuran, pyridine, acetonitrile, dimethylformamide or any other solvent which does not adversely affect the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under warming or heating, preferably under heating.
  • the present reaction includes, within its scope, the case that the dihalo(lower)alkyl group on R 2 , R 3 or R 4 is transformed to the oxo(lower)alkyl group during the reaction or at the post-treating step of the present process.
  • the object compound (I-b) or a salt thereof can be prepared by subjecting the compound (I-a) or a salt thereof to reduction.
  • the reduction may include, for example, chemical reduction with an alkali metal borohydride (e.g. sodium borohydride, etc.), and catalytic reduction with palladium catalysts (e.g. palladium on carbon, etc.), and the like.
  • alkali metal borohydride e.g. sodium borohydride, etc.
  • palladium catalysts e.g. palladium on carbon, etc.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N-dimethylformamide or a mixture thereof.
  • alcohol e.g. methanol, ethanol, propanol, etc.
  • tetrahydrofuran e.g. methanol, ethanol, propanol, etc.
  • dioxane dioxane
  • dimethyl sulfoxide dimethyl sulfoxide
  • N,N-dimethylformamide N,N-dimethylformamide
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the object compound (I) or a salt thereof can be prepared by reacting the compound (III) or a salt thereof with the compound (IV) or a salt thereof.
  • the present reaction is usually carried out in the presence of a base such as alkyl lithium (e.g. n-butyl lithium, etc.), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), di(lower)alkylamine (e.g. diisopropylamine, etc.), tri(lower)alkylamine (e.g. trimethylamine, triethylamine, etc.), pyridine or its derivative (e.g. picoline, lutidine, 4-dimethylaminopyridine, etc.), or the like.
  • alkyl lithium e.g. n-butyl lithium, etc.
  • alkali metal hydride e.g. sodium hydride, potassium hydride, etc.
  • di(lower)alkylamine e.g. diisopropylamine, etc.
  • tri(lower)alkylamine e.g. trimethylamine, triethylamine, etc.
  • the present reaction is usually carried out in a solvent such as dioxane, dimethyl sulfoxide, dimethylformamide, diethylformamide, dimethylacetamide, benzene, tetrahydrofuran, or any other solvent which does not adversely affect the reaction.
  • a solvent such as dioxane, dimethyl sulfoxide, dimethylformamide, diethylformamide, dimethylacetamide, benzene, tetrahydrofuran, or any other solvent which does not adversely affect the reaction.
  • the base to be used is liquid, it can also be used as a solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling, at ambient temperature or under heating.
  • the object compound (I-d) or a salt thereof can be prepared by subjecting the compound (I-c) or a salt thereof to removal reaction of the imino-protective group.
  • Suitable method for this removal may include conventional one which is capable of removing an imino-protective group on a tetrazolyl group such as hydrolysis, reduction, or the like.
  • the hydrolysis is preferably carried out in the presence of the base or an acid.
  • Suitable base may include, for example, an inorganic base such as alkali metal hydride (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate, (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetate (e.g. sodium acetate, potassium acetate, etc.), alkaline earth metal phosphate (e.g.
  • alkali metal hydride e.g. sodium hydroxide, potassium hydroxide, etc.
  • alkaline earth metal hydroxide e.g. magnesium hydroxide, calcium hydroxide, etc.
  • alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
  • alkali metal hydrogen phosphate e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.
  • an organic base such as trialkylamine (e.g. trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4,3,0]non-5-one, 1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,0]undecene-5 or the like.
  • the hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.
  • Suitable acid may include an organic acid (e.g. formic acid acetic acid, propionic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).
  • organic acid e.g. formic acid acetic acid, propionic acid, etc.
  • inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
  • the present hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof.
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • the starting compounds (II), (III) and (IV) are new and can be prepared by the methods of Preparations mentioned below or a similar manner thereto or a conventional manner.
  • the object compound (I) of the present invention can be isolated and purified in a conventional manner, for example, extraction precipitation, fractional crystallization, recrystallization, chromtography, and the like.
  • the object compound (I) thus obtained can be converted to its salt by a conventional method.
  • the object compound (I) of the present invention exhibits angiotensin antagonism such as vasodilating activity and is useful as an angiotensin II antagonist and effective to various angiotensin II mediated diseases such as hypertension (e.g. essential hypertension, renal hypertension, etc.), heart failure, and the like.
  • angiotensin antagonism such as vasodilating activity
  • angiotensin II antagonist and effective to various angiotensin II mediated diseases such as hypertension (e.g. essential hypertension, renal hypertension, etc.), heart failure, and the like.
  • the object compounds of the present invention are useful as therapeutical and/or preventive agents for cardiopathy (e.g. angina pectoris, arrhythmia, myocardial infarction, etc.), hyperaldosteronism, cerebral vascular diseases, senile dementia, ophthalimic diseases (e.g. glaucoma, etc.), and the like; and diagnostic agents to test the renin angiotensin system.
  • cardiopathy e.g. angina pectoris, arrhythmia, myocardial infarction, etc.
  • hyperaldosteronism e.g. angina pectoris, arrhythmia, myocardial infarction, etc.
  • cerebral vascular diseases e.g. senile dementia
  • ophthalimic diseases e.g. glaucoma, etc.
  • the bath was maintained at 37° C. and bubbled with 95% O 2 +5% CO 2 .
  • the strips was stretched with a resting force of 0.5 g, and the isometric contraction were recorded via force development transducer on an ink-writing recorder.
  • the preparation was equilibrated in Tyrode's solution mentioned above for 30 minutes, and then exposed to atropine (3.2 ⁇ 10 -7 g/ml). Five minutes later, the response for angiotensin II (1 ⁇ 10 -8 g/ml) was obtained and the preparation was washed a few times. This procedure was repeated twice.
  • control response After the last response for angiotensin II was obtained (control response), the preparation was washed, and the response for angiotensin II (10 -8 g/ml) was obtained in the presence of the test compound.
  • concentration of the test compound were 10 -7 , 10 -8 , 10 -9 , 10 -10 M
  • the test compound were added 3 minutes prior to adding angiotensin II.
  • Atropine was also added 5 minutes prior to adding angiotensin II.
  • the inhibition of the test compound for angiotensin II contraction were expressed as a percentage change to control response, and IC50 (M) was calculated.
  • the object compound (I) of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
  • pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
  • the pharmaceutical preparation may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade and the like.
  • auxiliary substances stabilizing agents, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like.
  • the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, a kind of diseases or conditions, a kind of the compound (I) to be applied, etc. In general amounts between 0.01 mg and about 500 mg or even more per day may be administered to a patient. An average single dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 20 mg, 50 mg, 100 mg of the object compound (I) of the present invention may be used in treating diseases.
  • Ethyl chloroformate (0.3 ml) was added to the mixture at the same temperature and the resulting mixture was stirred at -78° C. for half an hour, at 0° C. for one hour and then at ambient temperature for two hours. The reaction was quenched with aqueous saturated sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate.
  • 4-(4-Methoxycarbonylphenyl)-1H-pyrrole-3-carbonitrile (13.21 g) was prepared by reacting 4-methoxycarbonylcinnamonitrile (50 g) with p-tolylmethyl isocyanide (62.5 g) in a conventional manner.
  • the following compound was obtained by reacting 4-(4-methoxycarbonylphenyl)-1-methylpyrrole-3-carbonitrile with thionyl chloride, silica gel and carbon tetrachloride in a conventional manner.

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GB909020838A GB9020838D0 (en) 1990-09-25 1990-09-25 Condensed imidazole derivatives and process for preparation thereof
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GB909028216A GB9028216D0 (en) 1990-12-31 1990-12-31 Condensed imidazole derivatives and process for preparation thereof
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GB919103874A GB9103874D0 (en) 1991-02-25 1991-02-25 Heterocyclic derivatives
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GB919106956A GB9106956D0 (en) 1991-04-03 1991-04-03 Heterocyclic derivatives
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5376666A (en) * 1992-11-30 1994-12-27 The Du Pont Merck Pharmaceutical Company Angiotension-II receptor blocking, azacycloalkyl or azacycloalkenyl
US5451583A (en) * 1991-10-24 1995-09-19 American Home Products Corporation Substituted benzimidazoles and quinazolines as antihypertensives
US5455260A (en) * 1993-05-21 1995-10-03 Rhone-Poulenc Rorer Pharmaceuticals Inc. Aliphatic amino bis-aryl squalene synthase inhibitors
US20060100204A1 (en) * 2004-11-10 2006-05-11 Boehringer Ingelheim Pharmaceuticals, Inc. Anti-cytokine heterocyclic compounds
US20070027201A1 (en) * 2005-07-29 2007-02-01 Wyeth Use of progesterone receptor modulators
US20070027125A1 (en) * 2005-07-29 2007-02-01 Wyeth Cyanopyrrole-phenyl progesterone receptor modulators and uses thereof
WO2013032939A1 (en) * 2011-08-26 2013-03-07 Metabolex, Inc. Bicyclic agonists of gpr131 and uses thereof
US8703776B2 (en) 2011-06-15 2014-04-22 Cymabay Therapeutics, Inc. Agonists of GPR131 and uses thereof
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK

Families Citing this family (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5177074A (en) * 1991-03-26 1993-01-05 Merck & Co., Inc. Angiotensin ii antagonists incorporating a substituted thiophene or furan
TW274551B (zh) * 1991-04-16 1996-04-21 Takeda Pharm Industry Co Ltd
US5252574A (en) * 1991-04-26 1993-10-12 Merck & Co., Inc. Angiotensin II antagonists incorporating a substituted thiophene or furan
US5198438A (en) * 1991-05-07 1993-03-30 Merck & Co., Inc. Angiotensin ii antagonists incorporating a substituted thiophene or furan
GB9201789D0 (en) * 1992-01-28 1992-03-11 Fujisawa Pharmaceutical Co Heterocyclic derivatives
WO1993019067A1 (en) * 1991-09-12 1993-09-30 Fujisawa Pharmaceutical Co., Ltd. Imidazopyridine derivatives as angiotensin ii antagonists
US5354759A (en) * 1991-09-12 1994-10-11 Fujisawa Pharmaceutical Co., Ltd. Angiotenin II antagonizing heterocyclic compounds
WO1993018030A1 (en) * 1992-03-03 1993-09-16 Fujisawa Pharmaceutical Co., Ltd. Benzimidazole derivatives as angiotensin ii antagonists
US5364869A (en) * 1992-03-09 1994-11-15 Abbott Laboratories Heterocycle-substituted benzyaminopyridine angiotensin II receptor antagonists
EP0577025A3 (de) * 1992-07-01 1998-02-04 Hoechst Aktiengesellschaft Angiotensin-II-Rezeptorantagonisten zur Behandlung und Prophylaxe von koronaren Herzerkrankungen
EP0577023A3 (en) * 1992-07-01 1996-12-18 Hoechst Ag Angiotensin-ii receptor-antagonists for the treatment of arrhythmices
GB9218449D0 (en) 1992-08-29 1992-10-14 Boots Co Plc Therapeutic agents
WO1994005633A1 (en) * 1992-09-01 1994-03-17 Ciba-Geigy Ag 3-cyano-4-halogeno-2-(subst.phenyl)-pyrroles as pesticides and fungicides
ATE190613T1 (de) * 1992-10-13 2000-04-15 Searle & Co N-arylheteroarylalkyl-1-phenyl-imidazol-2-on verbindungen bei der behandlung von zirkulatorischen störungen
DE4236026A1 (de) * 1992-10-24 1994-04-28 Merck Patent Gmbh Imidazopyridine
WO1994013666A1 (en) * 1992-12-07 1994-06-23 Eisai Co., Ltd. Process for producing imidazopyridine derivative and intermediate
US5338740A (en) * 1993-07-13 1994-08-16 Pfizer Inc. Angiotensin II receptor antagonists
NZ309151A (en) * 1995-06-07 2000-01-28 Nippon Shinyaku Co Ltd a 3-substituted cyano or carbamoyl pyrrole derivative and pharmaceutical composition
US6143743A (en) 1997-07-03 2000-11-07 Dupont Pharmaceuticals Company Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders
US6124463A (en) * 1998-07-02 2000-09-26 Dupont Pharmaceuticals Benzimidazoles as corticotropin release factor antagonists
US6365589B1 (en) 1998-07-02 2002-04-02 Bristol-Myers Squibb Pharma Company Imidazo-pyridines, -pyridazines, and -triazines as corticotropin releasing factor antagonists
SE9903028D0 (sv) 1999-08-27 1999-08-27 Astra Ab New use
US7772271B2 (en) 2004-07-14 2010-08-10 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7781478B2 (en) 2004-07-14 2010-08-24 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7868037B2 (en) 2004-07-14 2011-01-11 Ptc Therapeutics, Inc. Methods for treating hepatitis C
EP1771169A1 (en) 2004-07-14 2007-04-11 PTC Therapeutics, Inc. Methods for treating hepatitis c
NZ553329A (en) 2004-07-22 2010-09-30 Ptc Therapeutics Inc Thienopyridines for treating hepatitis C
EA020466B1 (ru) 2007-06-04 2014-11-28 Синерджи Фармасьютикалз Инк. Агонисты гуанилатциклазы, пригодные для лечения желудочно-кишечных нарушений, воспаления, рака и других заболеваний
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
EP2810951B1 (en) 2008-06-04 2017-03-15 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
AR072297A1 (es) 2008-06-27 2010-08-18 Novartis Ag Derivados de indol-2-il-piridin-3-ilo, composicion farmaceutica que los comprende y su uso en medicamentos para el tratamiento de enfermedades mediadas por la sintasa aldosterona.
ES2624828T3 (es) 2008-07-16 2017-07-17 Synergy Pharmaceuticals Inc. Agonistas de la guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
CA2905435A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
CA2905438A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
PT3004138T (pt) 2013-06-05 2024-06-18 Bausch Health Ireland Ltd Agonistas ultrapuros de guanilato ciclase c, método de produção e utilização dos mesmos

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3130251A1 (de) * 1981-07-31 1983-02-17 A. Nattermann & Cie GmbH, 5000 Köln 6-(4-((omega)-(1-imidazolyl)-alkyl)-phenyl)-3-oxo -2,3,4,5-tetrahydro-pyridazine und deren saeureadditionssalze, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische praeparate
CA1338238C (en) * 1988-01-07 1996-04-09 David John Carini Angiotensin ii receptor blocking imidazoles and combinations thereof with diuretics and nsaids
US4916129A (en) * 1989-01-19 1990-04-10 E. I. Du Pont De Nemours And Company Combination β-blocking/angiotensin II blocking antihypertensives
IE64514B1 (en) * 1989-05-23 1995-08-09 Zeneca Ltd Azaindenes
IL94390A (en) * 1989-05-30 1996-03-31 Merck & Co Inc The 6-membered trans-nitrogen-containing heterocycles are compressed with imidazo and pharmaceutical preparations containing them
IL96019A0 (en) * 1989-10-31 1991-07-18 Fujisawa Pharmaceutical Co Imidazole derivatives,processes for the preparation thereof and pharmaceutical compositions containing the same
TW300219B (zh) * 1991-09-14 1997-03-11 Hoechst Ag

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts vol. 116(9), 194338y (1992); Abstract of Ger. Offen. 4023215 (1992). *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5451583A (en) * 1991-10-24 1995-09-19 American Home Products Corporation Substituted benzimidazoles and quinazolines as antihypertensives
US5376666A (en) * 1992-11-30 1994-12-27 The Du Pont Merck Pharmaceutical Company Angiotension-II receptor blocking, azacycloalkyl or azacycloalkenyl
US5455260A (en) * 1993-05-21 1995-10-03 Rhone-Poulenc Rorer Pharmaceuticals Inc. Aliphatic amino bis-aryl squalene synthase inhibitors
US20060100204A1 (en) * 2004-11-10 2006-05-11 Boehringer Ingelheim Pharmaceuticals, Inc. Anti-cytokine heterocyclic compounds
US7531560B2 (en) 2004-11-10 2009-05-12 Boehringer Ingelheim Pharmaceuticals, Inc. Anti-cytokine heterocyclic compounds
US7297713B2 (en) 2005-07-29 2007-11-20 Wyeth Cyanopyrrole-phenyl amide progesterone receptor modulators and uses thereof
US20070027125A1 (en) * 2005-07-29 2007-02-01 Wyeth Cyanopyrrole-phenyl progesterone receptor modulators and uses thereof
US20080064673A1 (en) * 2005-07-29 2008-03-13 Wyeth Cyanopyrrole-phenyl amide progesterone receptor modulators and uses thereof
US20070027201A1 (en) * 2005-07-29 2007-02-01 Wyeth Use of progesterone receptor modulators
US7652062B2 (en) 2005-07-29 2010-01-26 Wyeth Llc Cyanopyrrole-phenyl amide progesterone receptor modulators and uses thereof
US8703776B2 (en) 2011-06-15 2014-04-22 Cymabay Therapeutics, Inc. Agonists of GPR131 and uses thereof
WO2013032939A1 (en) * 2011-08-26 2013-03-07 Metabolex, Inc. Bicyclic agonists of gpr131 and uses thereof
US9593109B2 (en) 2011-08-26 2017-03-14 Cymabay Therapeutics, Inc. Bicyclic agonists of GPR131 and uses thereof
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK

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